This invention relates generally to generating analgesic effects by Transcranial Electrical Stimulation (TCES). More particularly, it relates to specific operating conditions for TCES and a method for using animal models to determine the optimal operating conditions.
The use of electrical currents for the purpose of producing narcosis or analgesia was pioneered by the French physiologist Leduc nearly 100 years ago. Over the next 70 years, several attempts were made to produce and maintain a state of general anesthesia by administering different parameters of electrical currents, applied to the skin of the subject""s head (i.e., transcranially and transcutaneously). However, due to the high intensity of current required to induce general anesthesia, these efforts were abandoned and superseded by attempts to produce analgesia, rather than general anesthesia, by application of electrical currents. Different types of Transcranial Electrical Stimulation (TCES) are suggested in the literature under a wide variety of names, including Cranial Electrotherapy Stimulation (CES), Low Current Electrostimulation, Auricular Microstimulation, and others [Limoge, 1999]. However, only French [Limoge, 1975] and Russian [Lebedev, 1988] currents are thought to produce an analgesic effect powerful enough to be utilized in clinical anesthesiology. Limoge currents consist of high frequency (166 kHz) intermittent bursts of bidirectionally balanced current xe2x80x9cpackedxe2x80x9d into trains. The current is applied transcranially and transcutaneously at 100 Hz for 4 msec at 6 msec intervals. These currents are described in part in U.S. Pat. No. 3,835,833, issued to Limoge. TCES with Limoge currents is applied through a frontal cathode and a pair of anodes located at the level of mastoid bones [Mantz, 1992]. TCES with Limoge current has been successfully used as part of an anesthetic management in a wide variety of surgical cases. It has been shown to:
increase the potency of nitrous oxide in humans by 30-40% [Stanley, 1982A];
reduce the need for opiates during neuroleptanesthesia by 50-80% [Stanley, 1982B];
potentiate opioid-induced analgesia in rats [Dougherty, 1989]; and
decrease minimum alveolar concentration (MAC) of halothane in rats [Mantz, 1992].
In the mid-1980""s, Russian investigators at the Pavlov Institute of Physiology in St. Petersburg determined parameters of TCES that produce a more profound analgesic effect than that observed with TCES with Limoge currents [Lebedev, 1983, 1988A, 1988B; Kovalev, 1987]. The major difference from Limoge currents was the use of a combination (2:1 or 3:1 ratio) of direct (DC) and alternating current (AC) of lower frequency (77-78Hz). The resultant current is also applied through frontal cathode and retromastoid anodes. The analgesic effect of xe2x80x9cLebedev currentxe2x80x9d was thought to be mediated by the AC, while the DC potentiated its action and eliminated the inherent seizure-provoking properties of AC [Rychkova, 1994]. This method of TCES has been successfully used in Russia in thousands of patients for different types of surgery, including cardiothoracic procedures, and in different age groups, including pediatrics [Katsnelson, 1987, 1989; Kartavkin, 1987; Zamiatnina, 1987]. So profound was the analgesic effect of TCES suggested by Russian researchers that intraoperative use of opioid narcotics in some cases could be completely avoided, and the analgesic effect extended into the immediate postoperative period [Lebedev, 1989]. This method has also been used successfully for treatment of chronic pain syndromes in awake subjects [Skorometz, 1987; Akimov, 1987; Gurchin, 1987; Kasimova, 1987]. Recently, Lebedev has restricted TCES stimulating parameters to administration of AC only, citing the same analgesic effect as with the combination of DC and AC [Lebedev, 1998]; however, no experimental data has been published to support that claim.
TCES with either Limoge or Lebedev current facilitates rapid recovery from general anesthesia without side effects such as respiratory depression, nausea and vomiting, itching, urinary retention, and immunosuppression [Stinus, 1990; Katsnelson, 1987]. Furthermore, both TCES modalities have been used successfully in the management of alcohol and opiate withdrawal states in awake patients [Auricombe, 1990; Krupitski, 1991]. Lebedev current has also been shown to promote tissue repair and decrease the incidence of surgical wound infections [Lebedev, 1998].
Despite these encouraging results, good controlled clinical studies are lacking. In addition, TCES studies in rats either failed to document prolongation of tail flick latency (TFL) with Limoge current [Stinus, 1990], or TFL responses were not studied [Lebedev, 1988]. TFL test is a standard measure of analgesia production in rats and mice, and correlates well with analgesic potency of drugs in humans. Lack of good controlled studies and consensus among researchers on the xe2x80x9cbestxe2x80x9d TCES stimulation parameters has contributed to the conflicting results between laboratories regarding the efficacy of TCES and the TCES mechanism of action [Alling, 1990]. Broad disagreement exists about optimal current intensity, electrode positioning and configuration, signal waveform, and frequency. However, it has been established that frequency is the most important variable in determining efficacy of analgesia production. It is also agreed that a tolerance effect may be established relatively rapidly: after a short time period, analgesic effects are no longer observed. In order to re-establish analgesia, the signal must be adjusted periodically.
Various researchers have developed different signal parameters for TCES. A series of U.S. patents have been issued to Kastrubin et al. and Nozhnikov et al., including U.S. Pat. Nos. 3,989,051; 4,121,593; 4,140,133; 4,185,640; 4,334,525; 4,383,522; and 4,724,841. Their devices, generally used for electroanesthesia, generate square pulses of varied current, duration, and frequency. Recommended frequencies are above 100 Hz, and stimulation is by a combination of direct and alternating current. The combination of AC and DC is also included in an electrotherapy method disclosed in U.S. Pat. No. 5,387,231, issued to Sporer. This method is primarily for pain relief through muscle relaxation and uses frequencies typically below 15 Hz and microampere current value that is much lower than typically used in TCES.
Other TCES parameters have been used for a variety of different applications. For example, currents somewhat similar to Limoge currents are employed for treating headaches, as described in U.S. Pat. Nos. 4,844,075 and 4,856,526, both issued to Liss et al. Other methods involve applying trains of pulsed current separated by off periods, as described in U.S. Pat. No. 4,646,744, issued to Capel, or trains of different frequencies, U.S. Pat. No. 5,593,432, issued to Crowther et al., in order to avoid acclimation of the nerves to the imposed signal. Both of these methods are directed toward drug addiction recovery.
Mechanism of TCES action remains unknown. Perhaps the most plausible explanation is that the electrical current causes depolarization of nerve terminals with the release of inhibitory neurotransmitter(s), interrupting nociceptive (pain receptor-related) processing. The identity of mediating neurotransmitter(s) and nociceptive pathway(s) involved has been widely debated; opioids, serotonin, and norepinephrine have each been implicated as a possible mechanism for the analgesic response to TCES [Airapetov, 1987; Lebedev, 19988A; Malin, 1989; Mantz, 1992].
Thorough studies are needed both to better understand the mechanism of TCES and to correctly determine the optimal operating conditions. Absent a neurobiologic substrate to explain observed analgesia, mainstream medical opinion remains skeptical, and TCES continues to be more of a curiosity than an established clinical practice outside of certain centers in France and Russia.
Accordingly, it is a primary object of the present invention to provide an improved Transcranial Electrical Stimulation (TCES) method employing optimal parameters that are not used in prior art methods.
It is a further object of the invention to provide a TCES method using parameters obtained from novel experimental studies. For the first time, electrode application in animal (rat) studies, from which optimal parameters are obtained, mimics electrode application in humans during clinical practice.
It is an additional object of the invention to provide a TCES method using parameters obtained from experimental studies that indicate that the mechanism of analgesia production may involve cutaneous nerve activation.
It is another object of the present invention to provide a TCES method using parameters obtained from randomized, blinded studies using accepted measures of analgesia production in rats.
These objects and advantages are attained by a method of eliciting analgesia in a human subject using Transcranial Electrical Stimulation (TCES) with novel operating parameters. The method is intended primarily for use during surgery or in the post-operative period, but is also useful for treating a wide variety of medical conditions, including chronic pain syndrome, alcohol withdrawal, opiate withdrawal, Attention Deficit Disorder, anxiety, depression, mood disturbance, Post-Traumatic Stress Disorder, immune system depression, decreased would healing, Parkinson""s disease, Alzheimer""s disease, neurological dysfunction, appetite disturbance, and sexual dysfunction. It can also be used to generate desired effects such as elevated mood and stimulated immune system. The present invention differs from prior art TCES in its use of parameters derived from animal studies that more closely mimic TCES application in humans, and are therefore more likely to duplicate the mechanism responsible for generating analgesia in humans.
The method is performed by removably fixing a first electrode and a pair of second electrodes to the skin of the subject""s head and delivering an electrical current to the electrodes. The current consists of a direct current (DC) component and rectangular current pulses supplied at a particular frequency within an effective range of 30-65 Hz. Preferably, the particular frequency is within a range of 40-60 Hz, and most preferably approximately 60 Hz. However, the optimal frequency depends on the particular human subject. At periodic intervals of 5-60 minutes, the frequency is changed to a different frequency within the effective range. Preferably, the frequency is also changed to a value outside of the effective range, but within 10-100 Hz, at longer intervals such as 15-60 minutes.
While frequency is believed to be the most important parameter for determining efficacy of analgesia production, other parameters are also important. The total current supplied, a sum of the DC component and a Mean Absolute Deviation (MAD) of the current pulses, preferably has a value between 0.2 and 20 mA, and most preferably between 2 and 10 mA. Preferably, the ratio between the value of the DC component and the MAD value of the alternating current is between 5:1 and 1:1, and most preferably approximately 2:1. Each AC pulse preferably has a duration of below approximately 8 msec, and most preferably of approximately 3.5 msec. The polarity of the current supplied can be switched at regular intervals such as 5-15 minutes.